
ショウジョウバエの体液性免疫応答は、JAK/STAT、NF-κB、GATAシグナル経路の相互作用によって調節されている。


coremsg

The two arms of innate immunity consist of the cell-mediated cellular defenses and the systemic humoral immune responses. Drosophila humoral immune defenses in the context of antimicrobial immunity, particularly the regulation and activation of antimicrobial peptide secretion from the fat body, have been studied extensively. How Drosophila regulates humoral immunity against another major natural enemy, the parasitoid wasp, is less well-characterized. In this study, we focused on a gene crucial in anti-parasitoid immunity, lectin-24A , which is specifically induced following parasitization. We found that a fluorescent reporter driven by the region upstream of lectin-24A showed localized posterior expression in the larval fat body, the Drosophila tissue mediating humoral immunity. Furthermore, with RNA sequencing of the anterior and posterior fat body sections, we found that components of JAK/STAT, GATA, and Toll pathways were regulated differentially in the anterior-posterior axis of the fat body and/or by infection. Predicted binding motifs for transcription factors in all three of these pathways were identified in the 444bp upstream region of the lectin-24A gene, where scrambling these motifs leads to reduced basal or induced expression of the fluorescent reporter. Investigating each of these pathways, we found that JAK/STAT, the GATA factor Pannier, and the NF-κB factor dorsal all modulate the expression of lectin-24A . The binding motifs associated with these transcription factors were also enriched in the upstream sequences of parasitism-induced genes in the fat body. Taken together, these results indicate that JAK/STAT, Pannier, and NF-κB signaling are involved in the regulation of lectin-24A and, more generally, Drosophila humoral anti-parasitoid immunity after infection.

### Competing Interest Statement

The authors have declared no competing interest.

A humoral immune response to parasitoid wasps in Drosophila is regulated by JAK/STAT, NF-κB and GATA

寄生蜂に対するショウジョウバエの体液性免疫応答は-jak-stat-nf-κb-gataによって調節される


寄生蜂に対するショウジョウバエの体液性免疫応答は、JAK/STAT、NF-κB、GATAによって調節される


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単一の抑制性 Ly49 受容体の発現で NK 細胞の免疫機能が十分に発揮される


Natural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor family in humans play a central role in NK cell immunity through recognition of MHC class I and related molecules. Functionally, these receptor families are involved in licensing and rejection of MHC-I-deficient cells through missing-self. The Ly49 family is highly polymorphic, making it challenging to detail the contributions of individual Ly49 receptors to NK cell function. Herein, we showed mice lacking expression of all Ly49s were unable to reject missing-self target cells in vivo , were defective in NK cell licensing, and displayed lower KLRG1 on the surface of NK cells. Expression of Ly49A alone on a H-2Dd background restored missing-self target cell rejection, NK cell licensing, and NK cell KLRG1 expression. Thus, a single inhibitory Ly49 receptor is sufficient to license NK cells and mediate missing-self in vivo .

### Competing Interest Statement

The authors have declared no competing interest.

Expression of a single inhibitory Ly49 receptor is sufficient to license NK cells for effector functions

単一の抑制性-ly49-受容体の発現で-nk-細胞の効果機能を引き起こすことが十分である


単一の抑制性 Ly49 受容体の発現で NK 細胞の効果機能を引き起こすことが十分である



結核感染時、好中球(Ly6G+細胞)が主要な IL-17 産生源となり、COX2 を介して結核の病態進行を促進する。IL-17 と COX2 を標的にすることで、BCG ワクチンの防御効果を高められる可能性がある。


The protective correlates of Mycobacterium tuberculosis ( Mtb ) infection-elicited host immune responses are incompletely understood. Here, we report pro-pathogenic crosstalk involving Ly6G+granulocytes (Ly6G+Gra), IL-17 and COX2. We show that in the lungs of Mtb -infected wildtype mice, either BCG-vaccinated or not, most intracellular bacilli are Ly6G+Gra-resident four weeks post-infection onwards. In the genetically susceptible IFNγ−/− mice, excessive Ly6G+Gra infiltration correlates with severe bacteraemia. Neutralizing IL-17 (anti-IL17mAb) and COX2 inhibition by celecoxib reverse Ly6G+Gra infiltration, associated pathology and death in IFNγ−/− mice. Surprisingly, Ly6G+Gra also serves as the major source of IL-17 in the lungs of Mtb -infected WT or IFNγ−/− mice. The IL-17-COX2-Ly6G+Gra interplay also operates in WT mice. Inhibiting RORγt, the key transcription factor for IL-17 production or COX2, reduces the bacterial burden in Ly6G+Gra, leading to reduced bacterial burden and pathology in the lungs of WT mice. In the Mtb -infected WT mice, COX2 inhibition abrogates IL-17 levels in the lung homogenates and significantly enhances BCG’s protective efficacy, mainly by targeting the Ly6G+Gra-resident Mtb pool. Furthermore, in pulmonary TB patients, high neutrophil count and IL-17 correlated with adverse treatment outcomes. Together, our results suggest that IL-17 and PGE2 are the negative correlates of protection, and we propose targeting the pro-pathogenic IL-17-COX2-Ly6G+Gra axis for TB prevention and therapy.

### Competing Interest Statement

The authors have declared no competing interest.

Ly6G+Granulocytes-derived IL-17 limits protective host responses and promotes tuberculosis pathogenesis

結核感染時の好中球由来-il-17-は宿主防御反応を抑制し-結核の病態進行を促進する


結核感染時の好中球由来 IL-17 は宿主防御反応を抑制し、結核の病態進行を促進する



Ctla-4は腸内免疫恒常性の維持に不可欠な役割を果たす。Ctla-4欠損はゼブラフィッシュにおいて炎症性腸疾患様の表現型を引き起こす。


Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. However, establishing a direct link between CTLA-4 and IBD has been challenging due to the early lethality of CTLA-4 knockout mice. In this study, we identified zebrafish Ctla-4 homolog and investigated its role in maintaining intestinal immune homeostasis by generating a Ctla-4-deficient ( ctla-4-/- ) zebrafish line. These mutant zebrafish exhibit reduced weight, along with impaired epithelial barrier integrity and lymphocytic infiltration in their intestines. Transcriptomics analysis revealed upregulation of inflammation-related genes, disturbing immune system homeostasis. Moreover, single-cell RNA-sequencing analysis indicated increased Th2 cells and interleukin 13 expression, along with decreased innate lymphoid cells and upregulated proinflammatory cytokines. Additionally, Ctla-4-deficient zebrafish exhibited reduced diversity and an altered composition of the intestinal microbiota. All these phenotypes closely resemble those found in mammalian IBD. Lastly, supplementation with Ctla-4-Ig successfully alleviated intestinal inflammation in these mutants. Altogether, our findings demonstrate the pivotal role of Ctla-4 in maintaining intestinal homeostasis. Additionally, they offer substantial evidence linking CTLA-4 to IBD and establish a novel zebrafish model for investigating both the pathogenesis and potential treatments.

### Competing Interest Statement

The authors have declared no competing interest.

All data generated or analyzed during this study are included in this article and its supplementary information files. The RNA-seq and scRNA-seq data for this study have been deposited in NCBI Gene Expression Omnibus (GEO) (<https://www.ncbi.nlm.nih.gov/geo/>) under accession numbers GSE255304 and GSE255303, respectively. The 16S rRNA sequencing data in this study have been deposited in the NCBI Sequence Read Archive (SRA) (<https://www.ncbi.nlm.nih.gov/sra/>) with an accession number of BioProject PRJNA1073727.

Unraveling the Role of Ctla-4 in Intestinal Immune Homeostasis: Insights from a novel Zebrafish Model of Inflammatory Bowel Disease

腸内免疫恒常性におけるctla-4の役割の解明-炎症性腸疾患の新規ゼブラフィッシュモデルからの洞察


腸内免疫恒常性におけるCtla-4の役割の解明：炎症性腸疾患の新規ゼブラフィッシュモデルからの洞察



TNFは感染症に対する免疫応答において重要な役割を果たすが、TNFを欠いていても感染症と戦えることが明らかになった。


Insights about the immune system of people who lack a defence protein.

People who lack the immune protein TNF can still fight infection

免疫タンパク質tnfを欠いていても感染症と戦える人々


免疫タンパク質TNFを欠いていても感染症と戦える人々



IL-2は、慢性感染においてCD8+ T細胞の効果機能を増強するが、CXCR5+ TPEX細胞の分化を抑制し、B細胞濾胞への局在を阻害する。


Cytotoxic CD8+ T cells, essential in combating viral infections and cancer, become dysfunctional from prolonged antigen exposure. Precursors of exhausted T (TPEX) cells are pivotal in sustaining immune responses in chronic diseases and mediating immunotherapy efficacy. They also control viral infection within B-cell follicles, facilitated by CXCR5 expression. How cytokines regulate TPEX cell fate and follicular entry is not well understood. We reveal that IL-2 treatment enhances CD8+ T cell effector functions in chronic LCMV infection but hinders CXCR5+ TPEX cell formation and infection control within B-cell follicles. Mechanistically, IL-2 suppresses TPEX cell differentiation in a STAT5 and BLIMP1-dependent manner. Using an IL-2 fusion protein targeting CD122, we shifted the differentiation towards CX3CR1+ T cells with increased effector function. Clinical observations with low-dose IL-2 in autoimmune disease confirmed IL-2’s inhibitory effect on CXCR5+ TPEX cells, underscoring IL-2’s crucial regulatory role and therapeutic potential in modulating TPEX and effector T cell generation.

### Competing Interest Statement

The authors have declared no competing interest.

IL-2 enhances effector function but suppresses follicular localization of CD8+ T cells in chronic infection

慢性感染におけるcd8-t細胞の機能と濾胞局在性を調整するil-2の役割


慢性感染におけるCD8+ T細胞の機能と濾胞局在性を調整するIL-2の役割



マラリア原虫のメロゾイト抗原とバリアント表面抗原に対する長期記憶B細胞の表現型には違いがある。


Plasmodium falciparum infections elicit strong humoral immune responses to two main groups of antigens expressed by blood-stage parasites: merozoite antigens that are involved in the erythrocyte invasion process and variant surface antigens that mediate endothelial sequestration of infected erythrocytes. Long-lived B cells against both antigen classes can be detected in the circulation for years after exposure, but have not been directly compared. Here, we studied the phenotype of long-lived memory and atypical B cells to merozoite antigens (MSP1 and AMA1) and variant surface antigens (the CIDRα1 domain of PfEMP1) in Ugandan adults before and after local reduction of P. falciparum transmission. After a median of 1.7 years without P. falciparum infections, the percentage of antigen-specific activated B cells declined, but long-lived antigen-specific B cells were still detectable in all individuals. The majority of MSP1/AMA1-specific B cells were CD95+CD11c+ memory B cells, which are primed for rapid differentiation into antibody-secreting cells, and FcRL5-T-bet- atypical B cells. On the other hand, most CIDRα1-specific B cells were CD95-CD11c- memory B cells. CIDRα1-specific B cells were also enriched among a subset of atypical B cells that seem poised for antigen presentation. These results point to differences in how these antigens are recognized or processed by the immune system and how P. falciparum -specific B cells will respond upon re-infection.

### Competing Interest Statement

The authors have declared no competing interest.

Differences in phenotype between long-lived memory B cells against Plasmodium falciparum merozoite antigens and variant surface antigens

マラリア原虫に対する長期記憶b細胞の表現型の違い-メロゾイト抗原とバリアント表面抗原の比較


マラリア原虫に対する長期記憶B細胞の表現型の違い - メロゾイト抗原とバリアント表面抗原の比較



炎症はB細胞、好中球、単球におけるLRRK2の発現と活性を増加させるが、樹状細胞と好酸球では減少させる。IL-4はB細胞でLRRK2の発現と活性を誘導する。


Mutations in Leucine-Rich Repeat protein Kinase 2 (LRRK2) are associated with Parkinson’s disease (PD) and Crohn’s disease (CD), but the regulation of LRRK2 during inflammation remains relatively unexplored. Here we developed a flow cytometry-based assay to assess LRRK2 activity in individual cells and created an EGFP-LRRK2-knock-in reporter mouse to analyse cell-specific LRRK2 expression. Using these tools, we catalogued LRRK2 level and activity in splenic and intestinal tissues. Inflammation increased LRRK2 expression and activity in B-cells, immature neutrophils and immature monocytes, but decreased these in dendritic cells and eosinophils. In mature neutrophils, inflammation stimulated LRRK2 activity but reduced EGFP-LRRK2 level. A kinase-activating PD-associated R1441C-LRRK2 mutation exacerbated inflammation-induced activation of LRRK2 specifically in monocytes and macrophages without affecting LRRK2 levels. Finally, we identified IL-4 as a novel factor that upregulated LRRK2 expression and activity in B-cells in vitro , replicating the inflammatory effects observed in vivo . Our findings provide valuable new insights into the regulation of the LRRK2 pathway in immune cells, crucial for understanding LRRK2 and its therapeutic potential in inflammatory diseases such as CD.

### Competing Interest Statement

MS and DRA received research funding for this project from Interline Therapeutics. AT is currently an employee of Amphista Therapeutics Ltd. MT is currently an employee of GlaxoSmithKline. The authors declare no other conflicts of interest. The funders did not play a role in the conceptualization, design, data collection, analysis, or preparation of the manuscript.

Regulation of Leucine-Rich Repeat Kinase 2 by inflammation and IL-4

炎症とil-4によるleucine-rich-repeat-kinase-2の調節


炎症とIL-4によるLeucine-Rich Repeat Kinase 2の調節



CCL28 は粘膜感染症の際に好中球の動員と活性化を促進し、病原体排除と組織損傷のバランスを調節する重要な因子である。


The chemokine CCL28 is highly expressed in mucosal tissues, but its role during infection is not well understood. Here we show that CCL28 promotes neutrophil accumulation to the gut of mice infected with Salmonella and to the lung of mice infected with Acinetobacter . Neutrophils isolated from the infected mucosa expressed the CCL28 receptors CCR3 and, to a lesser extent, CCR10, on their surface. The functional consequences of CCL28 deficiency were different between the two infections, as Ccl28 -/- mice were highly susceptible to Salmonella gut infection, but highly resistant to otherwise lethal Acinetobacter lung infection. In vitro , unstimulated neutrophils harbored pre-formed intracellular CCR3 that was rapidly mobilized to the cell surface following phagocytosis or inflammatory stimuli. Moreover, CCL28 stimulation enhanced neutrophil antimicrobial activity, production of reactive oxygen species, and formation of extracellular traps, all processes that were largely dependent on CCR3. Consistent with the different outcomes in the two infection models, neutrophil stimulation with CCL28 boosted the killing of Salmonella but not of Acinetobacter . CCL28 thus plays a critical role in the immune response to mucosal pathogens by increasing neutrophil accumulation and activation, which can enhance pathogen clearance but also exacerbate disease depending on the mucosal site and the infectious agent.

### Competing Interest Statement

The authors have declared no competing interest.

CCL28 modulates neutrophil responses during infection with mucosal pathogens

サルモネラ感染症とアシネトバクター肺炎における-ccl28-の役割-好中球の動員と活性化を通じた粘膜免疫応答の調節


サルモネラ感染症とアシネトバクター肺炎における CCL28 の役割 - 好中球の動員と活性化を通じた粘膜免疫応答の調節



ヒト上気道には、抗原特異的な記憶B細胞やT細胞を含む特徴的な免疫細胞集団が存在し、年齢に応じた変化が観察される。


This study of immunological memory diversity in the human upper airway provides new understanding of immune memory at a major mucosal barrier tissue in humans.

Immunological memory diversity in the human upper airway - Nature

ヒト上気道における免疫記憶の多様性